Selective inhibition of the neuronal isozyme of nitric oxide synthase (nNOS) has attracted significant interest as a novel strategy in developing therapeutics for the treatment of neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, and Huntington's disease. Efforts to design nNOS selective inhibitors include development of a stereospecific pyrrolidine-based inhibitor (1, FIG. 1), which showed great potency (Ki=5 nM) and extremely high selectivity for nNOS over closely related isoforms, endothelial NOS (eNOS, 3800 fold) and inducible NOS (iNOS, 1200 fold). Animal tests demonstrated that 1 could lead to a remarkable reduction in neurological damage to rabbit fetuses under hypoxic conditions, making 1 a strong candidate as a new drug for the treatment of neurodegenerative diseases.
Despite these and other discoveries, current and future research related to 1 is somewhat hindered by a complicated synthesis. In particular, the chiral pyrrolidine intermediate compound 2 (FIG. 1), achieved by a seven-step procedure of the prior art, is disadvantaged by expensive starting material(s), difficult chromatographic purification(s), and low overall yield (<2%). Moreover, utilization of racemic starting materials requires extra chiral resolution step(s) using either HPLC or chiral auxiliaries, which dramatically reduce the yield and efficiency. Therefore, the development of an efficient route to chiral core compound 2 remains an ongoing concern, the absence of which will continue to impede future investigations of inhibitor 1.